Cutanceous metabolic bio-activator

ABSTRACT

The invention relates to a cosmetic composition comprising a bio-active system which combines (i) a stable form in aqueous solution of ATP (adenosine-tri-phosphate) with optionally an ATP precursor, e.g. Gp 4 G (diguanosine tetraphosphate), or Ap 4 A (diadenosine tetraphosphate), and (ii) at least one biomimetic peptide comprising at most six amino acids, mimicking a cutaneous polypeptide or a cutaneous protein, or a biomolecule which is agonist or antagonist in relation to the aforementioned polypeptide or protein. According to the invention, the composition takes the form of a water-in-oil or oil-in-water emulsion, the bio-active system being included in the aqueous phase.

The present invention relates in general to cosmetic compositions.

The object of the present invention is to implement, via the cosmeticroute, a novel concept of cutaneous cell viability and/or stimulation,referred to by the term metabolic bioactivity. More particularly, theinvention relates to a cutaneous metabolic bioactivator.

An individual's lifestyle, the aggressive environment, and degenerativechronobiological evolution result in the biological functions and vitalfaculties of skin tissues becoming weaker over time. It thereforeappears to be essential to reestablish or maintain correct metabolic andcatabolic functioning of skin cells (keratinocytes, Langerhans cells,melanocytes, fibroblasts, etc.) so that they exchange with theirenvironment both exogenous energy and functional information.

An object of the present invention is therefore to increase or correct,naturally, the vast capacities of the skin by the combination of anexogenous supply of energy and of the stimulation of intercellularmessages. The synergy between this supply and this stimulation allowsthe skin to react against any attack or any disfunction, by activatingpreexisting metabolic mechanisms in the skin (molecular, cellular,tissue mechanisms) and optimizing, where appropriate, the interactionbetween the skin and the cosmetic active agent(s) provided bydermo-cutaneous care or treatments.

To this end, the present invention proposes a cosmetic compositioncomprising a bioactive system that combines, firstly, a stable form, inaqueous solution, of ATP (adenosine triphosphate) with, optionally, anATP precursor, for example Gp₄G (diguanosine tetraphosphate) or AP₄A(diadenosine tetraphosphate) and, secondly, at least one biomimeticpeptide comprising at most six amino acids, that mimics a cutaneouspolypeptide or a cutaneous protein, or a biomolecule that is an agonistor antagonist with respect to said peptide or to said protein.

The term “cosmetic composition” is intended to mean any compositionwhose function is to maintain, restore or improve the appearance of thesuperficial parts of the human body, mainly of the skin, whatever themethod of administration of said composition, i.e. via external topicaladministration or via internal oral administration.

The term “ATP precursor” is intended to mean any biochemical compoundthat is an intermediate in the de novo biosynthesis of ATP; preferably,the ATP precursor is Gp₄G (or diguanosine tetraphosphate) or Ap₄A(diadenosine tetraphosphate).

The term “biomimetic peptide” is intended to mean any peptide comprisingat most six amino acids, that mimics a cutaneous peptide or a cutaneousprotein, or a biomolecule that is agonist or antagonist with respect tosaid peptide or to said protein, which peptide or proteins plays a rolein or is involved in a cutaneous biosynthesis or the transfer ofcutaneous information.

Preferably, mimic peptides that are selected include the peptides orproteins that modulate the properties of the skin and immunity.

By way of example of the peptides or proteins of the skin that aremimicked by the peptides belonging to the bioactive system according tothe present invention, the following are selected:

-   -   1) neuromediators, including catecholamines (dopamine,        adrenaline, noradrenaline), endorphins (for example        beta-endorphin) and enkephalins (for example met-enkephalins);        by way of example, the following are selected:        -   somatostatin; cf. SEQ ID No. 3,        -   β-CGRP peptide; cf. SEQ ID No. 6,        -   β-endorphin; cf. SEQ ID No. 9,        -   leu-enkephalin; cf. SEQ ID No. 10,        -   met-enkephalin; cf. SEQ ID No. 11.    -   2) neuropeptides, for example:        -   substance P; cf. SEQ ID No. 1,        -   neuropeptide Y; cf. SEQ ID No. 2,        -   neurotensin; cf. SEQ ID No. 4,        -   α-CGRP peptide (calcitonin gene related peptide); cf. SEQ ID            No. 5,        -   neurokinins A and B,        -   GRP peptide (gastrin releasing peptide); cf. SEQ No. 7,        -   bradykinin; cf. SEQ ID No. 8.    -   3) neurohormones, for example:        -   α-MSH (melanocyte stimulating hormone) peptide; cf. SEQ ID            No. 12,        -   ACTH (adrenocorticotrophic hormone) peptide; cf. SEQ ID No.            13,        -   “prolactin releasing” peptide; cf. SEQ ID No. 14.

By way of example, a biomimetic peptide used according to the presentinvention mimics a peptide that is a substance P antagonist or a CGRPpeptide antagonist.

By way of example, a biomimetic peptide used according to the presentinvention mimics a peptide that is a somatostatin agonist.

By way of example, a biomimetic peptide used according to the presentinvention mimics a peptide that is a neuropeptide Y antagonist ormodulator.

By way of example, a biomimetic peptide used according to the presentinvention mimics a peptide that is a bradykinin receptor antagonist.

By way of example, a biomimetic peptide used according to the presentinvention mimics a peptide that is an α-MSH agonist or antagonist.

The term “mimic” or “mimicry” is intended to mean the characteristicaccording to which the peptide under consideration exerts, in vitro, andin particular in a composition according to the invention, a biologicaleffect similar or close to a biological function in vivo (for example inthe skin) of a reference biomolecule (for example peptide or protein).

Throughout the description and the claims, the term “peptide” should beunderstood to mean both a series of several unsubstituted amino acidsand a series of the same amino acids in which some, for example the N-terminal amino acid and/or the C-terminal amino acid, are substitutedwith a group or substituent, that may or may not be functional.

These peptides can be obtained either by conventional chemical synthesis(in solid phase or in homogeneous liquid phase), or by enzymaticsynthesis (Kullman et al., J. Biol. Chem. 1980, 255, 8234) from theconstitutive amino acids or from derivatives thereof.

These peptides can also be obtained by fermentation of a bacterialstrain that may or may not be modified by genetic engineering, so as toproduce the desired sequences or their various fragments.

Finally, these peptides can be obtained by extraction of proteins ofanimal or plant, preferably plant, origin, followed by a controlledhydrolysis that releases the peptides in question. Many proteins foundin plants are liable to contain advantageous sequences within theirstructure. Controlled hydrolysis makes it possible to free these peptidefragments.

In accordance with the present invention and according to a firstvariant, the bioactive system selected in the cosmetic compositionconstitutes, by itself, the active principle of the latter.

In this case, the biomimetic peptide selected makes it possible to“functionalize” the cosmetic composition; for example:

-   -   by selecting mimicry with α-MSH, a pigmenting activity is        obtained; conversely, by selecting mimicry with an α-MSH        antagonist, depigmenting activity is obtained;    -   by selecting mimicry with a peptide that is a substance P        antagonist, a soothing effect is obtained;    -   by selecting mimicry with a peptide that is a CGRP peptide        antagonist, an effect that inhibits irritations of neurogenic        origin is obtained;    -   by selecting mimicry with a peptide that is a bradykinin        antagonist, an effect that inhibits any intolerance or        sensitization is obtained.

According to a second variant, the bioactive system selected in thecosmetic composition potentiates one or more active principles, that arepresent in said composition.

By virtue of the invention, the bioactive system that characterizes thelatter makes it possible both to restore and/or to maintain the naturalactivity of the epidermis. This is particularly borne out if thecosmetic composition also contains skin nutrients and/or an aqueousphase that ensures viability of the skin cells.

The present invention also provides the following embodiments:

-   -   the stable form of ATP is a sodium salt, for example a disodium        salt of ATP,    -   the biomimetic peptide is functionally active in the        biosynthesis of a structural molecule of the skin or of an        enzyme present in the skin,    -   the biomimetic peptide is functionally active in the transfer of        information in the skin, and is, for example, a biologically        active fraction of a hormone or a cytokine present in the skin,    -   the biomimetic peptide is chosen from the group consisting of        histidine-β-alanyl (mimics superoxide dismutase), the peptide        R-Gly-Gln-Pro-Arg, the peptide Tyr-Arg, the peptide        R-Lys-Thr-Thr-Lys-Ser, and N-acetyl-Tyr-Arg-R (mimics        endorphins); R being any amino acid; the peptide        Lys-Thr-Thr-Lys-Ser, the peptide Ala-Arg-His-Leu-Phe-Tyr (mimics        alpha-MSH), and the peptide Gly-Gln-Asp-Pro-Val-Lys (mimics        elafin),    -   the biomimetic peptide is, for example, a dipeptide; in this        regard, the dipeptide may correspond to the formula Arg-R or        His-R, in which R is any amino acid; or else the dipeptide may        be in the form of an oligomer, of formula (R—R)_(n), with 1<n<3;        for example, the dipeptide corresponds to the formula        (Arg-Lys)_(n), with 1<n<3,    -   the biomimetic peptide is a tripeptide, for example        corresponding to the formula Gly-His-Lys, Gly-Glu-Pro or        Lys-Pro-Val,    -   the biomimetic peptide is a tetrapeptide, for example        corresponding to the formula Leu-Pro-Thr-Val, Lys-Thr-Ser-R or        Gly-Glu-Pro-R; R being any amino acid,    -   the biomimetic peptide is a pentapeptide, for example        Val-Ala-Lys-Leu-R; R being any amino acid,    -   the biomimetic peptide is a hexapeptide; by way of example, the        biomimetic peptide is Ala-R₁-R₂-R₃-Phe-Try, with R₁, R₂ and R₃        each being equal to any amino acid,    -   the cosmetic composition may comprise an amino acid, alongside        the bioactive system, said amino acid being chosen, for example,        from the group consisting of creatine, decarboxy carnosine, and        a glutamine, for example N-acetylglutamine,    -   the cosmetic composition according to the invention may        comprise, alongside the bioactive system, a protein, for example        chosen from the group consisting of superoxide dismutase,        endonucleases, photolyase, and cytokines from milk,    -   the bioactive system represents at most 10%, and preferably        between 1% and 10⁻⁷%, by weight of said composition,    -   the cosmetic composition according to the invention comprises at        least one cosmetic active principle potentiated by the bioactive        system according to the invention,    -   conventionally, the cosmetic composition is in the form of a        water-in-oil or oil-in-water emulsion, the bioactive system        being included, for example in solution, in the aqueous phase,    -   in the bioactive system according to the invention, the ATP and,        optionally, the ATP precursor represent at most 10%, and        preferably between 0.01% and 5%, by weight.

The effective amount of active agent(s) optionally present in acomposition according to the invention corresponds to the amountrequired to obtain the desired result, and the compositions according tothe invention depend on the use for which these compositions areintended.

A first category comprises the cosmetic compositions intended to beapplied to healthy skin in order to improve the esthetics and thecomfort thereof. Healthy skin can be defined as free of pathology, butwithout however being in perfect condition. This skin may have signs ofdryness, signs of irritation, wrinkles related to chronological oractinic aging, regions of hypersecretion of sebum, or regions ofhypopigmentation or of hyperpigmentation. In addition, healthy skin mayneed temporary or permanent photoprotection in order to withstandsunlight better.

Another category comprises the compositions intended to be applied toskin that has been made vulnerable by disease or medications, either ina preventive capacity or as a treatment continuing on from medicaltreatments.

The cosmetic compositions according to the present invention may alsocomprise at least one cosmetic active agent chosen from antioxidants,free-radical scavengers, α-hydroxy acids, vitamins, sunscreens orfilters, insect repellents and anti-inflammatories.

Of course, those skilled in the art will take care to choose this orthese optional active agent (s), and/or its (their) amount(s), in such away that the advantageous properties of the bioactive system accordingto the invention are not, or are not substantially, altered by theenvisioned addition(s). Preferably, a synergy between the bioactivesystem according to the invention and the active agent(s) underconsideration will be sought.

The compositions of the invention may be prepared according totechniques well known to those skilled in the art, in particular thoseintended for preparing emulsions of oil-in-water (O/W) or water-in-oil(W/O) type.

These compositions may in particular be provided in the form of a simpleemulsion or a complex emulsion: double (O/W or W/O) or triple (W/O/W orO/W/O), such as a cream, a milk, a gel or a cream-gel; of a powder or ofa solid tube, and may optionally be packaged as an aerosol and beprovided in the form of a mousse or of a spray.

When the cosmetic composition according to the invention is used for theprotection or the care of human epidermis, or as an antisun composition,it may be provided in the form of a suspension or of a dispersion insolvents or fatty substances, or in the form of a nonionic vesiculardispersion, or else in the form of an emulsion, preferably ofoil-in-water type, such as a cream or a milk, in the form of anointment, of a gel, of a cream-gel, of a solid tube, of a powder, of astick, of an aerosol mousse or of a spray.

When the cosmetic composition according to the invention is used forprotecting the hair, it may be in the form of a shampoo, of a lotion, ofa gel, of an emulsion, or of a nonionic vesicular dispersion, and mayconstitute, for example, a rinse-out composition, to be applied beforeor after shampooing, before or after dyeing or bleaching, before, duringor after permanent-waving or straightening the hair; this compositionmay also be provided in the form of a styling or treating lotion or gel,a blow-drying or hairsetting lotion or gel or a composition forpermanent-waving, straightening, dyeing or bleaching the hair.

When the composition is used as a makeup product for the nails, theeyelashes, the eyebrows or the skin, such as an epidermal treatmentcream, a foundation, a tube of lipstick, an eyeshadow, a blusher, amascara or an eyeliner, it may be provided in solid or pasty, anhydrousor aqueous form, such as oil-in-water or water-in-oil emulsions,nonionic vesicular dispersions or alternatively suspensions.

For the compositions according to the invention, the pH will bephysiological, between 4 and 7. When it is applied topically, thecomposition comprising at least one ATP and, optionally, a precursor,conjugated to at least one biomimetic peptide, can be applied to theface, the neck, the scalp, the mucous membranes, the nails, the body,the chest, the feet, the legs, or any other part of the body.

The compositions of the invention may also comprise conventionalcosmetic adjuvants, in particular chosen from fatty substances, organicsolvents other than those used specifically in the context of thepresent invention, emulsifiers, ionic or nonionic thickeners, soothingagents, opacifiers, stabilizers, emollients, silicones, antifoamingagents, moisturizers, vitamins, fragrances, preserving agents,surfactants, fillers, polymers, propellants, alkalifying or acidifyingagents, dyes or any other ingredients normally used in cosmetics, inparticular for producing compositions in the form of emulsions. By wayof example, the compositions according to the invention comprisescreening or reflecting agents, in the case of products intended to beused in the outside environment and in the sun.

The fatty substances may consist of an oil or a wax, or mixturesthereof, and they also comprise fatty acids, fatty alcohols and fattyacid esters. The oils may be chosen from animal, plant, mineral orsynthetic oils, and in particular from liquid petroleum jelly, paraffinoil, volatile or nonvolatile silicone oils, isoparaffins, polyolefins,and fluoro and perfluoro oils. Similarly, the waxes may be chosen fromanimal, fossil, plant, mineral or synthetic waxes that are known inthemselves.

Among polar oils, mention may be made of the oil known as “Finsolv TN”,tridecyl trimellitate, isononyl isononanoate, isopropyl myristate,decaprylyl carbonate, or Guerbet alcohol benzoates and hydroxybenzoates, such as the product called “Hallbrite BHB” from the companyCP Hall Company.

By way of indication, for the antisun formulations in accordance withthe invention that have an oil-in-water emulsion-type carrier, theaqueous phase (comprising in particular the hydrophilic screeningagents) generally represents from 50 to 95% by weight, preferably from70 to 90% by weight, relative to the entire formulation, the oily phase(comprising in particular the liophilic screening agents) representsfrom 5 to 50% by weight, preferably from 10 to 30% by weight, relativeto the entire formulation, and the (co)emulsifier(s) represent(s) from0.5 to 20% by weight, preferably from 2 to 10% by weight, relative tothe entire formulation.

In particular, the compositions according to the present invention canbe obtained in -the form of -an anhydrous composition which hastransparency and translucency properties that are entirely noteworthy.

A subject of the present invention is also the use of a cosmeticcomposition according to the present invention, for producing a skincare product, a makeup product for the skin, the lips and/or theinteguments, and an antisun product, and of a dermatological compositionfor skin care and/or treatment.

The composition according to the invention may be in the form of atinted dermatological or care composition for keratin materials such asthe skin, the lips and/or the integuments, in the form of an antisuncomposition or a body hygiene composition, in particular in the form ofa deodorant product or a makeup-removing product, in stick form. It may,in particular, be used as a care base for the skin, the integuments orthe lips (lip balms, for protecting the lips against the cold and/or thesun and/or the wind, or a care cream for the skin, the nails or thehair).

The composition of the invention may also be in the form of a coloredmakeup product for the skin, in particular a foundation, optionallyhaving care or treatment properties, a blusher, a makeup rouge, aneyeshadow, a concealer product, an eyeliner, a body makeup product; alip makeup product such as a lipstick, optionally having care ortreatment properties; a makeup product for the integuments such as thenails or the eyelashes, in particular in the form of a mascara cake, orfor the eyebrows and the hair, especially in the form of a pencil. Inparticular, the composition of the invention may be a cosmetic productcontaining, besides the bioactive system, cosmetic and/or dermatologicalactive agents.

A cosmetic composition according to the invention may also comprisepearlescent agents, pigments, or alternatively nanopigments (mean sizeof the primary particles: generally between 5 nm and 100 nm, preferablybetween 10 nm and 50 nm) of metal oxides that may or may not be coated,for instance nanopigments of titanium oxide (amorphous or crystallizedin rutile and/or anatase form), of iron oxide, of zinc oxide, ofzirconium oxide or of cerium oxide, and mixtures thereof, which are allUV-photoprotective agents well known in themselves. Conventional coatingagents are, moreover, alumina and/or aluminum stearate. Such coated oruncoated metal oxide nanopigments are in particular described in patentapplications EP-A-0518772 and EP-A-0518773.

Of course, the composition of the invention should be cosmetically ordermatologically acceptable, i.e. it should contain a nontoxicphysiologically acceptable medium and should be able to be applied tothe skin, the integuments or the lips of human beings. For the purposeof the invention, the term “cosmetically acceptable” is intended to meana composition with a pleasant appearance, odor and feel.

Trials

Trial No. 1

The biosimulatory activity of the L-citrullyl-Larginine peptide,associated or not associated with ATP, in the form of a disodium salt,on the cellular metabolism of normal human keratinocytes is evaluated.

1. Principle

The procedure consists in measuring the amounts of ATP in a culture offibroblasts in serum-deprived (2%) medium, in comparison with:

-   -   a medium enriched with citrullyl-arginine, at variable        concentrations,    -   a medium enriched with ATP, at variable concentrations,    -   a medium enriched with citrullyl-arginine and ATP, at variable        concentrations.

The aim of this trial is to evaluate the activating effect of themixture studied, associated or not associated with ATP disodium salt,with respect to ATP synthesis by normal human keratinocytes.

2. Method

Cell Culture

The trial is carried out on an in vitro culture of normal humankeratinocytes seeded at a density of 10⁵ cells/well in 6-well plates.

L-citrullyl-L-arginine

In order to determine the concentrations applicable in the context ofthe trial, a prior cell viability test is carried out on normal humankeratinocytes.

L-citrullyl-L-arginine is dissolved in water and the final concentrationis fixed at 0.1%.

6 dilutions of L-citrullyl-L-arginine from 10⁻⁴% to 10⁻²% are broughtinto contact with the cells for 24 h and 48 h. A “water” condition isrealized as a control.

For the trial, the L-citrullyl-L-arginine will be tested at the highest2 concentrations that allow the cell viability to be maintained at alevel greater than 80%, after 48 h of contact, i.e. 0.0001% and 0.01%.

UV B Irradiation

The keratinocytes, seeded in 6-well plates at a density of 10⁵cells/well, are cultured in standard medium (Epilife Sigma) for 48 h.Before irradiation, the culture medium is removed, the cells are rinsedwith PBS buffer, and 1 ml thereof is left in contact with the cells forthe irradiation. The keratinocytes are subjected to a UV B irradiation(312 nm) of 20 mJ/cm². An identical nonirradiated condition is realizedin parallel.

After irradiation (and on the nonirradiated parallel), the PBS isremoved and the cells are placed under the various conditions studied:

-   -   control of water in the culture medium,    -   0.001% L-citrullyl-L-arginine in the culture medium,    -   0.01% L-citrullyl-L-arginine in the culture medium.

Each condition is realized in triplicate.

After contact for 24 h or 48 h after irradiation, the conditionedculture supernatants are recovered. The amount of endothelin-1 secretedby the keratinocytes is measured on 100 μl of supernatant by means of anELISA technique (R&D Systems, Abingdon, UK). The endothelin-1 levels arecalculated by means of the standard curve prepared with synthesizedhuman endothelin-1. The results are expressed in pg of endothelin-1standardized with respect to the protein concentration (pg ET-1/mg ofproteins).

3. Results

The application of L-citrullyl-L-arginine for 24 h at the lowestconcentration tested (0.0001%) results in an increase in the basalsecretion of endothelin-1, by the keratinocytes (nonirradiatedcondition), of 20% compared with the “water” control. At the higherconcentration (0.01%), this activating effect is much more marked: 70%.

The UV B irradiation results in a 50% stimulation of the secretion ofendothelin-1 by the keratinocytes under the “water” control condition.After contact 24 h with 0.0001% L-citrullyl-L-arginine, the secretion ofendothelin-1 is increased by 6% compared with the irradiated “water”control. At 0.001%, the activating effect of the L-citrullyl-L-arginineis greatly increased: 28%.

The application of L-citrullyl-L-arginine for 48 h at the lowestconcentration tested (0.0001%) results in an increase in the basalsecretion of endothelin-1, by the keratinocytes (nonirradiatedcondition), of 26% compared with the “water” control. At the higherconcentration: 0.01%, this activating effect is much more marked: 82%.

The UV B irradiation results in a 40% stimulation of the secretion ofendothelin-1 by the keratinocytes under the “water” control condition.After contact for 48 h with 0.0001% L-citrullyl-L-arginine, thesecretion of endothelin-1 is increased by 4% compared with theirradiated “water” control. At 0.01%, the activating effect of theL-citrullyl-L-arginine is greatly increased: 63%.

4. CONCLUSION

Under the experimental conditions thus defined, for the dilutions andincubation times chosen, it is found that:

L-citrullyl-L-arginine, at a concentration of 0.01%, exerts aconsiderable activating effect on the secretion of endothelin-1 bynormal human keratinocytes.

In the presence of 0.01% ATP, the activating effect is stimulated by20%. There is clearly a synergistic effect between the molecules of ATPand of the L-citrullyl-L-arginine peptide.

The same studies carried out with ATP alone do not show any effect onendothelin-1 synthesis.

Trial No. 2

The effect of the combination ATP+dipeptides on the growth of normalhuman fibroblasts is studied.

The products studied are:

-   -   ATP, in the form of the disodium salt,    -   β-alanyl-L-histidine (carnosine),    -   citrullyl-arginine (exsy algine).        1. Objective of the Study

The objective of this trial is to evaluate the effect of the combinationATP+peptides, added to a culture medium, on the growth of animmortalized line of human fibroblasts, HaCaT cells.

In this study, two peptides are simultaneously and/or concomitantlycombined with ATP: β-alanyl-L-histidine (Dragoco) andL-citrullyl-L-arginine (Exsymol)

The study is carried out on a culture prepared in the standard culturemedium for HaCaT cells, DMEM (Sigma) in the presence of fetal calf serum(SVF) at 2 or 10%.

2. Techniques

The HaCaT cells are seeded at low density in a 96-well plate in thestandard medium (DMEM+10% SVF) and grow for 24 h after seeding in thismedium.

On the 2nd day, the cells are placed under the various conditionsstudied.

The test concentrations in terms of ATP, β-alanyl-L- histidine(Carnosine) and L-citrullyl-L-arginine (exsy- algine) are determinedsubsequent to preliminary cytotoxicity studies.

The following conditions are prepared:

-   -   A control condition: culture medium alone+SVF    -   A condition consisting of β-alanyl-L-histidine alone at 0.5%.    -   A condition consisting of L-citrullyl-L-arginine are known at        0.5%.    -   A condition consisting of ATP alone at 1 μg/ml.    -   A condition consisting of ATP (1 μg/ml)+β-alanyl-L-histidine        (0.5%).    -   A condition consisting of ATP (1 μg/ml)+L-citrullyl-L-arginine        (0.5%)    -   A condition consisting of ATP (1 μg/ml)+β-alanyl-L-histidine        (0.5%)+L- citrullyl-L-arginine (0.5%).

These various conditions are prepared both in the DMEM containing 2% SVFand the DMEM containing 10% SVF.

Each condition is prepared in triplicate. The media are not renewed inthe course of the experiment.

The cell density is evaluated 24 h after seeding of the cells, beforethe cells are brought into contact with the various study conditions(=T0), and the growth of the HaCaT cells is then evaluated on the 2nd,5th and 7th days of culture by means of the WST-1 conversion method(reading at 450 nm).

3. Results

The cell growth is objectified by measuring the cell viability atvarious times of the experiment. The results obtained give thepercentage cell viability calculated with respect to the initial celldensity at T0, for which it is estimated that the cell density is equalto 100%. The effects of the various products on cell growth are analyzedat the various times of the experiment, relative to the nontreatedcontrol at the same time of the experiment.

After 2 days of culture, a lack of growth with maintenance of cellviability is observed for the control condition, relative to the TOcontrol, which is explained by the switch into growth factor depletedmedium (2% SVF).

The addition of β-alanyl-L-histidine alone at a concentration of 0.5%greatly stimulates the cell growth (+22% relative to the nontreatedcontrol). At a concentration of 0.1%, no effect on growth is observed.

The addition of ATP alone substantially decreases cell viability.

The addition of ATP to the β-alanyl-L-histidine results in a suppressionof the inhibitory effect of the ATP on the cell viability and stimulatesthe latter beyond the level obtained with β-alanyl-L-histidine alone,for the 2 concentrations tested.

The addition of L-citrullyl-L-arginine alone, at a concentration of 0.1%and 0.5%, does not stimulate cell growth (+5%) relative to thenontreated control.

After 5 days of culture, a slight decrease in cell viability isobserved, relative to T0, due to the culture being maintained in growthfactor-depleted medium.

The stimulatory effect on cell growth of β-alanyl-L-histidine at aconcentration of 0.5% (+12%) is again observed.

The addition of ATP alone substantially decreases cell viability, whicheffect disappears subsequent to the addition of 0.5%β-alanyl-L-histidine.

L-citrullyl-L-arginine alone still does not stimulate cell growth,whatever the concentration used.

4. CONCLUSION

Under the experimental conditions thus defined and at the concentrationstested, it appears that the addition of ATP alone substantiallydecreases the viability of normal human fibroblasts after 2 to 5 days ofcontact (−5 to −10%).

The combination ATP+β-alanyl-L-histidine cancels the inhibitory effectof the ATP on cell viability and stimulates the latter beyond the levelobtained with β-alanyl-L-histidine alone, which exerts a stimulatoryeffect on cell growth at a concentration of 0.5%.

The combination ATP+L-citrullyl-L-arginine exerts no stimulatory effecton cell growth, whatever the concentration used.

Trial No. 3

1. Cell Culture

Cultures of normal human melanocytes (MHNs) are prepared from fore skinsof infants and of newborns suffering from phimosis. The melanocytesobtained from skin fragments are placed in MCDB 153 medium (Sigma StLouis, Mo., USA) supplemented with 30 μg/ml of bovine pituitary extract(BPE) (Life Technologies, Paisley, England), 2% of fetal calf serum(SVF) (Dominique Dutscher, Brumath, France), 16 nM ofphorbol-12-myristate-13-acetate (Sigma), 5 μg/ml of insulin and 1.1 μMof hydrocortisone (Sigma). The cultures are maintained in an incubatorat 37° C. and-in-an atmosphere containing 5% CO₂. Pure cultures ofmelanocytes are obtained after 2 to 3 weeks.

2. Contact Time, Irradiation of Cells and Preparation of Slides

All the compositions tested are solubilized in DMSO at the maximumconcentrations permitted. Preliminary trials are carried out in order todetermine the subtoxic concentrations on the keratinocytes. The finalconcentration of DMSO is always less than 2%.

The melanocytes are brought into contact with the product for 30 min at37° C., and are then irradiated with UVA radiation. The UVA irradiationsare generated by means of a Bio-Sun UV-irradiator (Vilbert Lourmat,Marne la Vallée). This device is equipped with monochromatic lamps thatemit a wavelength of 312 nm and/or 365 nm. The lamps deliver acalculated energy by means of an RMW-365/312 radiometer. The energiesdelivered are 0.8 J/cm² for the UVA range. The “comet” assay is carriedout immediately after exposure. Two types of controls are included inthese experiments:

-   -   negative controls: melanocytes that are not treated but are        irradiated with UVA radiation; melanocytes treated for 30 min        with the composition tested, but not irradiated.    -   Positive control: melanocytes that are not treated but are        irradiated.

After treatment with a typsin/EDTA mixture (0.05%/0.02%) for 2 to 3minutes, the cultures are 15 recovered by centrifugation and placed inPBS buffer without Ca++ and without Mg++ (Sigma). Following a secondcentrifugation, the cells (4.5-5.0×10⁴ cells) are suspended in 0.5% lowmelting point (LMP) agarose (Sigma). The mixture is directly depositedonto microscope slides coated with a prelayer of agarose (1.6%) driedovernight at ambient temperature and freshly precoated with a secondlayer of agarose (0.8%).

3. The Comet Assay (Dry Slide Technique) and Enzymatic Treatment

The protocol for the comet assay is that of De Meo et al. [1],incorporating the “dry slide” technique [2]. After the irradiations, theslides are placed in a lysis bath (2.5 M NaCl, 100 mM Na₂EDTA, 10 mMTris-HCl, pH 10, 1% of sodium sarcosinate, 1% of triton X-100 and 10% ofDMSO). The cell lysis is performed at 4° C. for 60 minutes, followed bydenaturation of the DNA at ambient temperature for 20 min in a stronglyalkaline solution (1 mM Na₂EDTA and 300 mM NaOH, pH>13.0). Afterelectrophoresis (25 V, 300 mA) for 20 min., the slides are neutralizedwith the Tris-HCl buffer (0.4 M; pH 7.4) and dehydrated in absoluteethanol or methanol.

4. Microscopic Observation and Image Analysis

The slides are stained with ethidium bromide solution (75 μl of 2 μg/ml)and observed using a BH2-RFL fluorescence microscope (Olympus, Japan)equipped with a 20BG-W dichroic filter (excitation: 515-560 nm;emission: 590 nm) and with an Apo D-Plan 20× objective. The imageanalysis is carried out with a high sensitivity monochrome CCD camera(Cohu 4912-5000) coupled to a Matrox IP-8 acquisition board. The entireassembly is controlled by means of the Fenestra Komet software (KineticImaging, Liverpool, UK, version 3.1).

A total of 100 cells per sample (50 cells/slide) is analyzed. Theparameter used is “tail DNA”, which is defined as the percentage of DNAin the tail of the “comet”. For each series of experiments, a negativecontrol (nonirradiated cells) and a positive control (irradiated cellswithout composition tested) are included.

5. Statistical Analysis

Nonlinear regressions based on a χ² function are calculated directlyfrom the TM (tail moment) distribution frequencies for each sample.Specifically, Bauer et al. [3] have recently shown that thesedistributions follow a χ² function. This method is based on an analysisof the distribution according to a χ² law.

The factor n (also called ω² TM), which represents the degree of freedomof the function, is directly correlated with the degree of damage (meanTM). The factor n varies from 2 (intact cells) to 15 (cells extremelydamaged, with a Gaussian distribution frequency).

The degree of freedom (n) can be used as an indicator of DNA damage. Thedistribution frequencies are calculated with the Excel 97 tabulator(Microsoft) and the nonlinear regressions are calculated with the TableCurve 2D software (Jandel Scientific, version 5.0).

6. REFERENCES

-   [1] De Méo M, M. Laget M, Castegnaro M, Duménil G. Genotoxic    activity of potassium permanganate acidic sodium. Mutation Res.    1991; 260; 295-306.-   [2] Klaude M, Ericksson S, Nygren J, Annstrom G. The comet assay:    mechanism and technical consideration. Mutation Res. 1996; 363;    89-96.-   [3] Bauer E, Recknagel R D, Fiedler U, Wollweber L, Bock C,    Greulich K. O. The distribution of the tail moments in single cell    electrophoresis (comet assay) obeys a chi-square (χ²) not a gaussian    distribution. Mutation Res. 1998;-398: 101-110.    7. Degree of Protection by the Compositions Tested

The results according to the table below are obtained. Degree ofComposition OTM-χ² protection (%) NI 2.08 ± 0.02 — NI + ATP (4 mM) 2.08± 0.02 — NI + Citru (4 mM) 2.06 ± 0.02 — NI + ATP (4 mM) + Citru 2.07 ±0.02 — (4 mM) UVA 9.16 ± 0.32 0.00% UVA + ATP (4 mM) 6.31 ± 0.38 14.6%(NS) UVA + Citru (4 mM) 2.22 ± 0.20 67.7% UVA + ATP (4 mM) + Citru 2.11± 0.04 99.6% (4 mM)OTM-χ² = tail moment χ²: degree of freedom of the function calculated bynonlinear regression of the normalized frequency of distribution of theOTMs. The probability of the models in all cases is P < 0.001.NI: nonirradiated melanocytes.NI + ATP: nonirradiated melanocytes pretreated with ATP (4 mM) for 30min.NI + Citru: nonirradiated melanocytes pretreated with citrullyl arginine(4 mM) for 30 min.UVA: melanocytes irradiated with UVA radiation (0.8 J/cm²).UVA + ATP: melanocytes irradiated with UVA radiation (0.8 J/cm²) andpretreated with ATP (4 mM) for 30 min.UVA + Citru: melanocytes irradiated with UVA radiation (0.8 J/cm²) andtreated with citrullyl arginine (4 mM) for 30 min.NS: difference not significant between UVA + Citru and UVA + ATP.

The degree of protection by citrullyl arginine is much greater than thatby ATP. The synergy between the ATP molecule and the peptide is veryclear.

The examples that follow illustrate the invention without, however,limiting the scope thereof.

EXAMPLES Example 1 Antiwrinkle Cream

Sucrose stearate 0.5-6% Sucrose distearate 0.5-6% ATP disodium salt  0.01-0.05% Diguanosine tetraphosphate (Gp4G) 0.5-1% Caprylic/caprictriglyceride   3-15% Caprylic/capric/succinic triglyceride   3-15%Ceramides 3 0.05-1%  Ascorbyl palmitate  0.01-0.1% Tocopheryl acetate0.05-1%  Urea 0.5-2% Calcium chloride  0.05-0.5% Magnesium chloride 0.05-0.5% β-Alanyl-L-histidine (Carnosine) 0.5-1% Gly-His-Lys (peptidepowder) 10-5 ppm Serine 0.2-2% Glycerol 0.5-3% Citric acid   0.1-0.5%Trisodium citrate   0.5-1.5% Vitamin A palmitate   0.1-0.5%Phospholipids   0.1-0.4% Superoxide dismutase 0.5-2% Sodium hyaluronate0.5-3% Potassium sorbate   0.2-0.5% Sclerotium gum   0.1-0.5% Xanthangum   0.1-0.5% Water qs 100% Fragrance qs Preserving agents qs

Example 2 Moisturizing Milk

Diguanosine tetraphosphate (Gp4G) 0.5-1% Phospholipids   3% Ceramide 3 0.1% Vitamin A palmitate 0.15% Steareth-20  0.2% Steareth-2 1 to 3%Methyl paraben 0.25% Calcium chloride 0.01% Magnesium chloride 0.01%Water qs 100% Cetostearyl alcohol 2 to 4% Myristyl myristate 2 to 4%Isopropyl myristate   4% Glycerol   1% L-Citrullyl-L-arginine 0.1 to2%   Dimethicone  0.5% Lanolinic alcohols  0.5% Propyl paraben 0.25%

Example 3 Moisturizing Cream

ATP disodium salt 0.01-0.05% Sorbitan oleate 3.5% Polysorbate 80 2 to 4%Wheatgerm oil   3% Sweet almond oil   5% Isopropyl myristate  12%Phospholipids 0.5% Ceramide 3 0.1% Polyacrylamide & C₁₄₋₁₃ isoparaffin &  2 to 3.5% Laureth-7 Vitamin A palmitate 0.1% Tocopherol 0.05%  SodiumPCA 0.5% Diguanosine tetraphosphate (Gp4G) 0.5-1%   Sodium hyaluronate0.1% Water qs 100% L-Citrullyl-L-arginine 0.1 to 2%   Preserving agentsqs Fragrance qs

Example 4 Protective Suntan Cream

ATP Disodium salt 0.01-0.05% Octyl methoxycinnamate 6.00% (Neo HeliopanAV) Butylmethoxydibenzoylmethane 3.00% (Parsol 1789) Octyltriazone 2.00%(Uvinul T150) Di (C₁₂₋₁₃) alkyl tartrate 8.00% (Cosmacol ETI) Cetylalcohol 0.50% Dimethicone 0.50% Coco caprylate/caprate 8.00%PVP/eicosene copolymer 2.00% Potassium cetyl phosphate 2.00% Methyl andpropyl paraben 0.25% Disodium EDTA 0.10% BHT 0.05% Carbomer 10.00% Diguanosine tetraphosphate (Gp4G) 0.5-1%   Alanyl-L-histidine(Carnosine) 0.8-1%   Propylene glycol 5.00% Potassium hydroxide 4.05%Phenylbenzimidazolesulfonic acid 2.00% (Eusolex 232) Tocopheryl acetate2.50% Panthenol 1.00% MSH (Ala-His-Lys-Phe-Tyr)  0.0001-0.00001%Photolyase  0.1% Water qs 100% Fragrance qs

Example 5 Photoprotective and Repair Suncream

ATP Disodium salt 0.01-0.05% Ethoxydiglycol and cucumber 8.00% Di-C₁₂₋₁₃alkyl tartrate 5.00% (Cosmacol ETI) Octyl methoxycinnamate 5.00% (ParsolMCX) Butylmethoxydibenzoylmethane 2.00% (Parsol 1789) Dimethiconetrimethylsiloxysilicate 3.00% Tocopheryl acetate 0.20% Sucrosedistearate 5.00% Hexylene glycol 5.00% Butyl, methyl, propyl 0.40%paraben + phenoxyethanol L-Citrullyl-L-arginine 0.1 to 2% Water qs 100%Diguanosine tetraphosphate (Gp4G)   1-1.5% MSH (Ala-His-Lys-Phe-Tyr) 0.0001-0.00001% Endonuclease  0.2% Alanyl-L-histidine (Carnosine)0.5-1%   Fragrance qs

Example 6 Soothing Photorepair Milk

Mineral oil 2.00% Diguanosine tetraphosphate (Gp4G) 0.5-1% Di-C₁₂₋₁₃alkyl tartrate 4.00% (Cosmacol ETI) Octyl stearate 3.00%Isoamyl-p-methoxycinnamate 5.00% (Parsol MCX)Butylmethoxydibenzoylmethane 1.00% (Parsol 1789) Polyglyceryl-3diisostearate 4.00% Glyceryl PEG-20 laurate 1.00% Carbomer  0.4%Propylene glycol 2.00% Preserving agents 0.50% Xanthan gum 0.30%Triethanolamine 0.85% Phenylbenzimidazolesulfonic acid  2.5% (NeoHeliopan Hydro) Acetyl tyrosine 2.00% Alanyl-L-histidine (Carnosine)0.5-1% Gly-His-Lys (peptide powder) 10-5 ppm Water qs 100% Fragrance qs

Example 7 Desensitizing Face Cream

Caprylic/capric/succinic triglyceride  1 to 10% Ascorbyl palmitate 0.01to 0.1%  Glyceryl stearate 1 to 5% Stearic acid 1 to 5% Tocopherolacetate 0.1 to 1%   Carpylic/capric triglyceride  1 to 15% ATP disodiumsalt 0.01-0.05% Pyridoxine 0.01 to 0.05% Citric acid 0.1 to 0.5% Zincgluconate 0.1 to 1%   Trisodium citrate   1 to 2.5%L-Citrullyl-L-arginine 0.1 to 2%   Diguanosine tetraphosphate (Gp4G)0.5-1%   Glycerol 1 to 4% Vitamin A palmitate 0.01 to 1%   d-Panthenol0.1 to 1%   Rhamnose 0.1 to 1%   L-Fucose 0.01 to 1%  Lactoferrin/lactoperoxidase 0.01 to 1%   Superoxide dismutase 0.01 to1%   Polyacrylamide/C₁₃₋₁₄ 0.2 to 1%   isoparaffin/laureth-7 Water qs100%

Example 8 Soothing Body Milk

Acrylic acid polymer 0.1-1.5% Glycyrrhetinic acid 0.1-1%  Triethanolamine 0.1-2%   Butylene glycol 0.5-4%   ATP disodium salt0.01-0.05% Ascorbyl palmitate 0.01 to 0.1%  Tocopherol acetate 0.1 to1%   Pyridoxine 0.01 to 0.05% Citric acid 0.1 to 0.5% Zinc gluconate 0.1to 1%   Trisodium citrate   1 to 2.5% L-Arginine 0.1 to 2%   Vitamine Apalmitate 0.01 to 1%   d-Panthenol 0.1 to 1%   L-Fucose 0.1 to 1%  Lactoferrin/lactoperoxidase 0.01 to 1%   Alanyl-L-histidine (Carnosine)0.5-1%   R-Gly-Gln-Pro-Arg 15-20 ppm Superoxide dismutase 0.01 to 1%  Potassium sorbate 0.1 to 0.6% Preserving agents qs Water qs 100%

Example 9 Soothing Cream for Greasy Skin

Propylene glycol 1-8% Sorbitan monolaurate 0.5-5%   Dimethicone copolyol0.1-5%   Salicylic acid 0.01-0.5 % Disodium EDTA 0.05-0.5%  Diguanosinetetraphosphate (Gp4G) 0.5-1%   ATP disodium salt 0.01-0.05% Zincgluconate 0.01-1%   Ascorbyl palmitate 0.01 to 0.1%  Tocopherol acetate0.1 to 1%   Pyridoxine 0.01 to 0.05% Citric acid 0.1-0.5% Sodiumchloride 0.1-1.5% Trisodium citrate   1 to 2.5% L-Arginine 0.1 to 2%  Vitamin A palmitate 0.01 to 1%   d-Panthenol 0.1 to 1%   Rhamnose 0.1 to1%   L-Fucose 0.01 to 1%   Lactoferrin/lactoperoxidase 0.01 to 1%  Gly-His-Lys (peptide powder) 10-5 ppm Superoxide dismutase 0.01 to 1%  Preserving agents qs Water qs 100%

Example 10 Makeup-Removing Lotion

Diguanosine tetraphosphate (Gp4G) 1-2% ATP disodium salt 0.1-0.5%Trisodium citrate 1 to 2.5% Glycerol 0.5-3%   Hexylene glycol 4-5%d-Panthenol 0.1 to 1%   Alanyl-L-histidine (Carnosine) 0.5-1%  Preserving agents (methyl paraben and qs phenoxyethanol) Water qs 100%

Sequence Description

SEQ ID No. 1 H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂: (11 A)SEQ ID No. 2 H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂: (36 AA) SEQ ID No. 3H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser- Cys-OH: (14 AA)SEQ ID No. 4 pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH:(13 AA) SEQ ID No. 5H-Ala-Cys-Asp-Thr-Ala-Thr-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH₂:(37 AA) SEQ ID No. 6H-Ala-Cys-Asn-Thr-Ala-Thr-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Met-Val-Lys-Ser-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH₂: (37 AA) SEQ ID No. 7H-Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met- NH₂: (27 AA)SEQ ID No. 8 H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH: (9 AA) SEQ ID No.9 H-Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys Lys-Gly-Glu-OH:(31 AA) SEQ ID No. 10 H-Tyr-Gly-Gly-Phe-Leu-OH: (5 AA) SEQ ID No. 11H-Tyr-Gly-Gly-Phe-Met-OH: (5 AA) SEQ ID No. 12Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val- NH₂: (13 AA) SEQID No. 13 H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro-Asn-Gly-Ala-Glu-Asp-Glu-Ser-Ala-Glu-Ala-Phe-Pro-Leu-Glu-Phe-OH: (39 AA) SEQ ID No. 14H-Ser-Arg-Thr-His-Arg-His-Ser-Met-Glu-Ile-Arg-Thr-Pro-Asp-Ile-Asn-Pro-Ala-Trp-Tyr-Ala-Ser-Arg-Gly-Ile-Arg-Pro-Val-Gly-Arg-Phe-NH₂: (31 AA)

1. A cosmetic composition comprising a bioactive system that combines,firstly, a stable form, in aqueous solution, of ATP (adenosinetriphosphate) with, optionally, an ATP precursor, for example Gp₄G(diguanosine tetraphosphate) or Ap₄A (diadenosine tetraphosphate) and,secondly, at least one biomimetic peptide comprising at most six aminoacids, that mimics a cutaneous polypeptide or a cutaneous protein, or abiomolecule that is an agonist or antagonist with respect to saidpolypeptide or to said protein.
 2. The composition as claimed in claim1, characterized in that the stable form is a sodium salt of ATP, forexample a disodium salt.
 3. The composition as claimed in claim 1,characterized in that the biomimetic peptide is functionally active inthe biosynthesis of a structural molecule of the skin, or of an enzymepresent in the skin.
 4. The composition as claimed in claim 1,characterized in that the biomimetic peptide is functionally active inthe transfer of information in the skin, and is, for example, abiologically active fraction of a hormone or cytokine present in theskin.
 5. The composition as claimed in claim 1, characterized in thatthe biomimetic peptide is chosen from the group consisting ofhistidine-β-alanyl, the peptide R-Gly-Gln-Pro-Arg, the peptide Tyr-Arg,the peptide R-Lys-Thr-Thr-Lys-Ser, N-acetyl-Tyr-Arg-R, the peptideLys-Thr-Thr-Lys-Ser, the peptide Ala-Arg-His-Leu-Phe-Tyr (or alpha-MSH),and the peptide Gly-Gln-Asp-Pro-Val-Lys (or elafin); R being any aminoacid.
 6. The composition as claimed in claim 1, characterized in thatthe biomimetic peptide is a dipeptide.
 7. The composition as claimed inclaim 6, characterized in that the dipeptide corresponds to the formulaArg-R or His-R, in which R is any amino acid.
 8. The composition asclaimed in claim 6, characterized in that the dipeptide is in the formof an oligomer, of formula (R—R)_(n), with 1<n<3.
 9. The composition asclaimed in claim 8, characterized in that the dipeptide corresponds tothe formula (Arg-Lys)_(n), with 1<n<3.
 10. The composition as claimed inclaim 1, characterized in that the biomimetic peptide is a tripeptide.11. The composition as claimed in claim 10, characterized in that thetripeptide is Gly-His-Lys or Gly-Glu-Pro.
 12. The composition as claimedin claim 1, characterized in that the biomimetic peptide is atetrapeptide.
 13. The composition as claimed in claim 12, characterizedin that the tetrapeptide is Leu-Pro-Thr-Val or Lys-Thr-Ser-R orGly-Glu-Pro-R; R being any amino acid.
 14. The composition as claimed inclaim 1, characterized in that the biomimetic peptide is a pentapeptide,for example Val-Ala-Lys-Leu-R; R being any amino acid.
 15. Thecomposition as claimed in claim 1, characterized in that the biomimeticpeptide is a hexapeptide.
 16. The composition as claimed in claim 15,characterized in that the biomimetic peptide is Ala-R₁-R₂-R₃-Phe-Try,with R₁, R₂ and R₃ each equal to any amino acid.
 17. The composition asclaimed in claim 1, characterized in that it comprises an amino acid,for example chosen from the group consisting of creatine, decarboxycarnosine and a glutamine, for example N-acetylglutamine.
 18. Thecomposition as claimed in claim 1, characterized in that it comprises aprotein, for example chosen from the group consisting of superoxidedismutase, endonucleases, photolyase and cytokines from milk.
 19. Thecomposition as claimed in claim 1, characterized in that the bioactivesystem represents at most 10%, and preferably between 1% and 10⁻⁷%, byweight of said composition.
 20. The composition as claimed in claim 1,characterized in that it comprises at least one cosmetic activeprinciple potentiated by the bioactive system.
 21. The composition asclaimed in claim 1, characterized in that it is in the form of awater-in- oil or oil-in-water emulsion, the bioactive system beingincluded in the aqueous phase.
 22. The composition as claimed in claim1, characterized in that the bioactive system, the ATP and, optionally,the ATP precursor represent at most 10%, and preferably between 0.01%and 5%, by weight.